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Benign Melanocytic Nevus

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Todd W Ridky – 1st expert on this subject based on the ideXlab platform

  • abstract 1239 cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Research, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Todd W Ridky

    Abstract:

    The CDKN2A locus on chromosome 9p21 encodes two tumor suppressors: the cyclin dependent kinase inhibitor p16INK4a and the MDM2 regulator p14ARF. Homozygous deletion of this locus is among the most common genetic events in human cancer across tissues, with the resultant selective advantage to cancer cells generally attributed to the loss of CDKN2A proteins, which help maintain functional Rb and p53. However, in greater than 90% of cancer tissues harboring CDKN2A deletion, the adjacent CDKN2B gene encoding the p15 cyclin dependent kinase inhibitor, is also deleted. The degree to which CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in common, Benign Melanocytic nevi (moles) expressing the constitutively active BRAF(V600E) oncogene. A large percentage of melanomas develop in continuity with these pre-existing nevi, suggesting that Nevus melanocytes are not permanently senescent, and can serve as tumor-initiating cells upon acquisition of additional genetic changes. By examining primary melanocytes isolated directly from freshly excised Benign human nevi, as well as normal primary melanocytes engineered to inducibly express BRAF(V600E), we link BRAF activation to a TGFβ-dependent p15 induction that arrests nevi in their pre-malignant state. We also use the primary Nevus cells to establish a new genetically-defined, human in vivo melanoma xenograft model, which maximizes medical relevance by utilizing the naturally occurring melanoma precursor cells in a native 3-dimensional environment. With this approach, we show that p15 depletion in Benign nevi promotes progression to melanoma, establishing the reversibility of Nevus melanocyte growth arrest, and the functional importance of CDKN2B loss in human cancer. Citation Format: Andrew McNeal, Kevin Liu, Vihang Nakhate, Christopher Natale, Brian Capell, Tzvete Dentchev, Shelley Berger, Meenhard Herlyn, John Seykora, Todd W. Ridky. CDKN2B loss promotes progression from Benign Melanocytic Nevus to melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1239. doi:10.1158/1538-7445.AM2015-1239

  • cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Discovery, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Elizabeth K Duperret, Todd W Ridky

    Abstract:

    Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in Benign Melanocytic nevi, contributes to maintaining Nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E) activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Further, we engineer human skin grafts containing Nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from Benign Nevus to melanoma.

Andrew Mcneal – 2nd expert on this subject based on the ideXlab platform

  • abstract 1239 cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Research, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Todd W Ridky

    Abstract:

    The CDKN2A locus on chromosome 9p21 encodes two tumor suppressors: the cyclin dependent kinase inhibitor p16INK4a and the MDM2 regulator p14ARF. Homozygous deletion of this locus is among the most common genetic events in human cancer across tissues, with the resultant selective advantage to cancer cells generally attributed to the loss of CDKN2A proteins, which help maintain functional Rb and p53. However, in greater than 90% of cancer tissues harboring CDKN2A deletion, the adjacent CDKN2B gene encoding the p15 cyclin dependent kinase inhibitor, is also deleted. The degree to which CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in common, Benign Melanocytic nevi (moles) expressing the constitutively active BRAF(V600E) oncogene. A large percentage of melanomas develop in continuity with these pre-existing nevi, suggesting that Nevus melanocytes are not permanently senescent, and can serve as tumor-initiating cells upon acquisition of additional genetic changes. By examining primary melanocytes isolated directly from freshly excised Benign human nevi, as well as normal primary melanocytes engineered to inducibly express BRAF(V600E), we link BRAF activation to a TGFβ-dependent p15 induction that arrests nevi in their pre-malignant state. We also use the primary Nevus cells to establish a new genetically-defined, human in vivo melanoma xenograft model, which maximizes medical relevance by utilizing the naturally occurring melanoma precursor cells in a native 3-dimensional environment. With this approach, we show that p15 depletion in Benign nevi promotes progression to melanoma, establishing the reversibility of Nevus melanocyte growth arrest, and the functional importance of CDKN2B loss in human cancer. Citation Format: Andrew McNeal, Kevin Liu, Vihang Nakhate, Christopher Natale, Brian Capell, Tzvete Dentchev, Shelley Berger, Meenhard Herlyn, John Seykora, Todd W. Ridky. CDKN2B loss promotes progression from Benign Melanocytic Nevus to melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1239. doi:10.1158/1538-7445.AM2015-1239

  • cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Discovery, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Elizabeth K Duperret, Todd W Ridky

    Abstract:

    Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in Benign Melanocytic nevi, contributes to maintaining Nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E) activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Further, we engineer human skin grafts containing Nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from Benign Nevus to melanoma.

John T Seykora – 3rd expert on this subject based on the ideXlab platform

  • abstract 1239 cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Research, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Todd W Ridky

    Abstract:

    The CDKN2A locus on chromosome 9p21 encodes two tumor suppressors: the cyclin dependent kinase inhibitor p16INK4a and the MDM2 regulator p14ARF. Homozygous deletion of this locus is among the most common genetic events in human cancer across tissues, with the resultant selective advantage to cancer cells generally attributed to the loss of CDKN2A proteins, which help maintain functional Rb and p53. However, in greater than 90% of cancer tissues harboring CDKN2A deletion, the adjacent CDKN2B gene encoding the p15 cyclin dependent kinase inhibitor, is also deleted. The degree to which CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in common, Benign Melanocytic nevi (moles) expressing the constitutively active BRAF(V600E) oncogene. A large percentage of melanomas develop in continuity with these pre-existing nevi, suggesting that Nevus melanocytes are not permanently senescent, and can serve as tumor-initiating cells upon acquisition of additional genetic changes. By examining primary melanocytes isolated directly from freshly excised Benign human nevi, as well as normal primary melanocytes engineered to inducibly express BRAF(V600E), we link BRAF activation to a TGFβ-dependent p15 induction that arrests nevi in their pre-malignant state. We also use the primary Nevus cells to establish a new genetically-defined, human in vivo melanoma xenograft model, which maximizes medical relevance by utilizing the naturally occurring melanoma precursor cells in a native 3-dimensional environment. With this approach, we show that p15 depletion in Benign nevi promotes progression to melanoma, establishing the reversibility of Nevus melanocyte growth arrest, and the functional importance of CDKN2B loss in human cancer. Citation Format: Andrew McNeal, Kevin Liu, Vihang Nakhate, Christopher Natale, Brian Capell, Tzvete Dentchev, Shelley Berger, Meenhard Herlyn, John Seykora, Todd W. Ridky. CDKN2B loss promotes progression from Benign Melanocytic Nevus to melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1239. doi:10.1158/1538-7445.AM2015-1239

  • cdkn2b loss promotes progression from Benign Melanocytic Nevus to melanoma
    Cancer Discovery, 2015
    Co-Authors: Andrew Mcneal, Vihang Nakhate, Christopher A Natale, Brian C Capell, Tzvete Dentchev, Shelley L Berger, Meenhard Herlyn, John T Seykora, Elizabeth K Duperret, Todd W Ridky

    Abstract:

    Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in Benign Melanocytic nevi, contributes to maintaining Nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E) activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Further, we engineer human skin grafts containing Nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from Benign Nevus to melanoma.